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  • Androgen and Antiandrogen-Mediated Hormonal Carcinogenesis

    Paul M.D. Foster, Ph.D.

    foster2@niehs.nih.gov

    mailto:foster2@niehs.nih.gov
  • Hormonally-Induced Reproductive Tumors: Relevance of Rodent Bioassays

    May 22-24, 2006 in Raleigh, NC

    http://ntp.niehs.nih.gov/files/AgendaRTWpostREV1.pdf

    http://ntp.niehs.nih.gov/files/AgendaRTWpostREV1.pdf
  • OverviewOverview zz Androgens and antiandrogensAndrogens and antiandrogens Androgen receptorAndrogen receptor SteroidogenesisSteroidogenesis

    zz Prostate cancerProstate cancer Animal and human differencesAnimal and human differences Androgen sensitivityAndrogen sensitivity

    zz Testicular CancerTesticular Cancer Leydig cell tumorsLeydig cell tumors Animals versus humansAnimals versus humans Potential modes of actionPotential modes of action Developmental exposuresDevelopmental exposures

    PMD Foster 3

  • Androgen Receptor ActionAndrogen Receptor Action

    AR Antagonist

    PMD Foster 4

  • Production of AndrogensProduction of Androgens Testes: Target Organ:

    Secrete Testosterone Testosterone to DHT

    OH

    Cholesterol HO

    CH3

    CH3

    O

    CH3

    CH3 OH

    Testosterone O

    CH3

    CH3 O

    Androstenedione Dihydro-testosterone

    (DHT)

    O

    CH3

    CH3

    H H

    Adrenal Glands: Secrete Androstenedione Converting Enzyme:

    5-alpha-Reductase

    PMD Foster 5

  • Production of AndrogensProduction of Androgens Testes: Target Organ:

    Secrete Testosterone Testosterone to DHT

    OH

    Cholesterol HO

    CH3

    CH3

    O

    CH3

    CH3 OH

    Testosterone O

    CH3

    CH3 O

    Androstenedione Dihydro-testosterone

    (DHT)

    O

    CH3

    CH3

    H H

    Adrenal Glands: Secrete Androstenedione Converting Enzyme:

    5-alpha-Reductase= Steroid enzyme inhibition

    PMD Foster 6

  • PMD Foster 7

    Comparison of Rat and Human Prostate Anatomy

    Human Rat

    Human prostate is not lobular; - Has minimal ventral glandular tissue - Urethra and vas deferens transverse the prostate - Mesodermal component in central lobe: around vas

    Rodent prostate is lobular: VP, DP, LP, AP - Dorso-lateral lobe most resembles human prostate peripheral zone histologically & embryologically - AP similarity to central zone mesodermal stroma - Significance of lobular location for human PCa is uncertain - No periurethral region transition zone

  • PROSTATE CANCERPROSTATE CANCER The Magnitude of the ProblemThe Magnitude of the Problem

    zz The most prevalent nonThe most prevalent non--cutaneouscutaneous cancer in American males.cancer in American males. zz Second leading cause of cancer deaths in malesSecond leading cause of cancer deaths in males of similar magnitudeof similar magnitude

    to breast cancer in females and AIDS.to breast cancer in females and AIDS. zz Ethnicity a major risk factor: 2:Ethnicity a major risk factor: 2:1 ratio of incidence in African1 ratio of incidence in African--

    AmeriAmericcan males vs Caucasian inan males vs Caucasian in US.US. Asian males have lowestAsian males have lowest incidence.incidence.

    zz AgeAge--related incidence: up to 30% ofrelated incidence: up to 30% of males over 50 years harbor silenmales over 50 years harbor silentt prostate cancer.prostate cancer.

    zz % of men in US (1993% of men in US (1993--1995) developing invasive1995) developing invasive PCaPCa with age:with age: BirthBirth -- 39 years: < 1 in 10,00039 years: < 1 in 10,000 4040 -- 59 years: 1.83 % (1 in 45)59 years: 1.83 % (1 in 45) 6060 -- 79 years: 14.79 % (1 in 7)79 years: 14.79 % (1 in 7) Birth to Death: 17.00 % (1 in 6)Birth to Death: 17.00 % (1 in 6)

    zz Hormone DependenceHormone Dependence:: 100% organ100% organ--confined disease initially AR positive & androgen dependent.confined disease initially AR positive & androgen dependent. AllAll PCaPCa progress toprogress to androgen independenceandrogen independence (AI) yet 90% retain AR.(AI) yet 90% retain AR.

    PMD Foster 8

  • Morphologic continuum from normal prostatic epitheliumMorphologic continuum from normal prostatic epithelium through increasing grades of PINthrough increasing grades of PIN to early invasive carcinomato early invasive carcinoma

    Bostwick DG, Brawer MK: Prostatic intraepithelial neoplasia and early invasion in prostate cancer. Cancer 59:788-794, 1987

    PMD Foster 9

  • Role of AR in AndrogenRole of AR in Androgen--IndependentIndependent PCaPCa

    PMD Foster From Nelson et al, NEJM, 2003 10

  • Evidence for the Involvement of EstrogensEvidence for the Involvement of Estrogens in Normal and Diseased Prostatein Normal and Diseased Prostate

    zz Presence ofPresence of ERER andand ERER in normal prostate and prostatein normal prostate and prostate tumorstumors

    zz Estrogens known to directly induceEstrogens known to directly induce squamous metaplasiasquamous metaplasia ofof prostate epithelium in humans, rodents, dogs, monkeys, bulls,prostate epithelium in humans, rodents, dogs, monkeys, bulls, sheep, goatssheep, goats

    zz Estrogens are recognized carcinogens by the InternationalEstrogens are recognized carcinogens by the International Agency for Research on CancerAgency for Research on Cancer

    zz Estrogen induction of BPH andEstrogen induction of BPH and PCaPCa in animal modelsin animal models BPH in dogs :E + DHT or E + 3BPH in dogs :E + DHT or E + 3--diol (Walsh)diol (Walsh) PCaPCa in rats: E + T in rats (Noble)in rats: E + T in rats (Noble)

    zz Increasing E/T ratios in aging malesIncreasing E/T ratios in aging males

    PMD Foster 11

  • Other Pathways implicated inOther Pathways implicated in Prostate CancerProstate Cancer

    zzAromataseAromatase AromataseAromatase is the CYP enzyme convertingis the CYP enzyme converting

    testosterone to Etestosterone to E22.. AromataseAromatase knock out mouse has an enlargedknock out mouse has an enlarged

    prostate.prostate. Supports role of ESupports role of E22/T balance in/T balance in prostate disease.prostate disease.

    zzGH/ IGFGH/ IGF--1 pathway1 pathway Regulates proliferation of prostate cells inRegulates proliferation of prostate cells in

    cultureculture Elevated IGFElevated IGF--1 associated with increased risk1 associated with increased risk

    PMD Foster 12

  • NTP Historical Control for ProstateNTP Historical Control for Prostate NeoplasiaNeoplasia

    PMD Foster 13

  • Prostate Aden~oma in a Rat

    PMD Foster 14

  • Evidence in Animals forEvidence in Animals for Testosterone InvolvementTestosterone Involvement

    zz Exogenous TExogenous T low incidence oflow incidence of PCaPCa in some ratin some rat strains (T as carcinogen)strains (T as carcinogen)

    zz Exogenous T + carcinogenExogenous T + carcinogen high incidence ofhigh incidence of PCaPCa in some rat strains (T as promoter)in some rat strains (T as promoter)

    zz Early castrationEarly castration incidence ofincidence of PCaPCa zz PCaPCa prone LW rats haveprone LW rats have serum T.serum T.

    PMD Foster 15

  • Control Rat TestisControl Rat Testis

    Leydig cells

    Sertoli cells

    PMD Foster 16

  • Leydig Cell EMLeydig Cell EM

    PMD Foster 17

  • Endocrine and Paracrine Control ofEndocrine and Paracrine Control of Leydig Cell FunctionLeydig Cell Function

    PituitaryPituitary

    Sertoli cell

    Leydig cell

    cholesterol

    testosterone Liver

    Hydroxylation

    Conjugation

    Excretion

    LH T

    T

    factors

    Testis

    PMD Foster 18

  • Leydig Cell TumorsLeydig Cell Tumors zzRodentRodent Tumors tend to be benign and occur late in 2Tumors tend to be benign and occur late in 2--

    year bioassays.year bioassays. Background incidence rates can vary in ratsBackground incidence rates can vary in rats

    from 95% (Ffrom 95% (F--344).344). Influence ofInfluence of in uteroin utero exposure?exposure?

    zzHumanHuman Leydig cell tumors do occur (

  • Definition of a Rodent LeydigDefinition of a Rodent Leydig Cell TumorCell Tumor

    zz NTP:NTP: An aggregate of Leydig cells greater thanAn aggregate of Leydig cells greater than 11 seminiferous tubule in diameter.seminiferous tubule in diameter.

    zz STP:STP: An aggregate of Leydig cells greater thanAn aggregate of Leydig cells greater than 33 seminiferous tubules in diameter.seminiferous tubules in diameter.

    zz There is a continuum of response from Leydig cellThere is a continuum of response from Leydig cell hyperplasia (which can be diffuse or nodular) to thehyperplasia (which can be diffuse or nodular) to the presence of Leydig cell tumors (adenomas).presence of Leydig cell tumors (adenomas). Diagnosis is based on size and will be dependent onDiagnosis is based on size and will be dependent on where the Xwhere the X--section is obtained.section is obtained.

    zz Similar diagnostic size criteria do not apply forSimilar diagnostic size criteria do not apply for humans.humans.

    PMD Foster 20

  • Rat LC Hyperplastic NoduleRat LC Hyperplastic Nodule

    PMD Foster 21

  • Leydig Cell TumorLeydig Cell Tumor

    PMD Foster 22

  • Human Leydig Cell MicronodulesHuman Leydig Cell Micronodules

    Holm et al J Pathol 2003; 199: 378386.

    PMD Foster 23

  • PMD Foster 24

    Mode Of Action Species (strain) LC Response

    Examples

    Androgen Receptor Antagonists

    Rat (Wistar, CD)

    Adenoma Biclutamide, Flutamide, Linuron, Procymidone, Vinclozolin

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